Glucocorticoid-induced TNFR-related protein (GITR), a member of the TNFR superfamily, is expressed in many components of the innate and adaptive immune system (see, e.g., Hanabuchi et al. (2006) Blood 107:3617-3623; and Nocentini and Riccardi (2005) Eur. J. Immunol. 2005. 35:1016-1022). Its membrane expression is increased following T cell activation (Hanabuchi, supra; and Nocentini and Riccardi, supra); its triggering co-activates effector T lymphocytes and modulates regulatory T cell (Treg) activity (see, e.g., McHugh, et al. (2002) Immunity 2002. 16:311-323; Shimizu, et al. (2002) Nat. Immunol. 3:135-142; Ronchetti, et al (2004) Eur. J. Immunol. 34:613-622; and Tone, et al. (2003) Proc. Natl. Acad. Sci. USA 100:15059-15064.
GITR is activated by GITR ligand (GITRL), which is mainly expressed on APC and has been suggested to deliver signals by its cytoplasmic domain, although further studies are necessary to define the biochemical signaling (Nocentini, supra; Ronchetti, supra; Suvas, et al. (2005) J. Virol. 79:11935-11942; and Shin, et al. (2002) Cytokine 19:187-192).
GITR activation increases resistance to tumors and viral infections, is involved in autoimmune/inflammatory processes and regulates leukocyte extravasation (Nocentini supra; Cuzzocrea, et al. (2004) J. Leukoc. Biol. 76:933-940; Shevach et al. (2006) Nat. Rev. Immunol. 6:613-618; Cuzzocrea, et al. (2006) J. Immunol. 177:631-641; and Cuzzocrea et al. (2007) FASEB J. 21:117-129).
The need exists for improved methods and compositions for the treatment of immune and proliferative disorders, e.g., tumors and cancers, by use of agents that modulate GITR activity. Preferably, such agonists would have a high affinity for the target molecule, and would be able to stimulate GITR signaling at relatively low doses. Preferably, such methods and compositions would be highly specific for GITR, and not interfere with the activity of other receptors. Preferably, such methods and compositions would employ agonists suitable for modification for the delivery of cytotoxic payloads to target cells, but also suitable for non-cytotoxic uses. Preferably, such methods and compositions would employ antibodies modified to limit their antigenicity when administered to a subject in need thereof.